(a) Field of the Invention
The invention relates to novel antibodies and their use for detecting, imaging, staging, treating and monitoring of prostate cancer, and/or metastasis thereof. Furthermore, the invention also relates to novel pharmaceutical compositions for the treatment of prostate cancer.
(b) Description of Prior Art
The prostate gland is affected by various significant pathological conditions as benign growth (BPH), infection (prostatitis), and neoplasia (prostate cancer).
Prostate cancer is the second most frequently diagnosed cancer in Canadian and American men, after non-melanoma skin cancer, which is rarely fatal. More importantly, after lung cancer, prostate cancer is the most common cause of cancer-related death. The risk of developing prostate cancer increases significantly with age, particularly for men over 50. For men under 50 years of age the disease is uncommon and death from it is rare.
Prostate cancer accounts for an estimated 28% of newly diagnosed cancer in Canadian men and more than 12% of cancer-related deaths. The current lifetime risk of a Canadian man being diagnosed with prostate cancer is about 1 in 8. In the United States, prostate cancer accounts for approximately 32% of male cancer diagnoses and 14% of cancer deaths. Studies in the United States suggest that the incidence rate may be approaching 1 in 6 men.
Because the incidence of prostate cancer increases with age, it is clear that the burden of this illness will increase dramatically in the coming decades. The aging of the population, particularly the baby boomers, will have important long-term implications for the number of new cases diagnosed. Demographic trends in the next two decades will increase the population at risk for prostate cancer. Statistics Canada projections indicate that the population of men over age 50 will increase from 3.9 million in 1999 to 5.6 million in 2011 (44% increase) and 6.3 million in 2016 (62% increase). The United States Census Bureau projections indicate that the population of men over age 50 will increase from 33.8 million in 1999 to 45.8 million in 2011 (36% increase) and 50.7 million in 2016 (50% increase). The American Cancer Society predicts that there will be about 180,400 new cases of prostate cancer in the United States in the year 2000, and about 31,900 American men will die of the disease.
As a consequence of the expected increases in the number of cases of prostate cancer in the coming years due to rising incidence rates and the aging North American population, more resources will likely be allocated to screening men over 50 for this condition, therefore yielding an increase in the number of cases of identified prostate cancer.
Prostate cancer often exhibits a long latency period. However, it is believed that prostate cancer often remains undetected. Also, because it possesses a high metastatic potential to bone and the lymph nodes, with <10% of individuals diagnosed with prostate cancer also demonstrated, by radionuclide scans, to have bone metastasis, prompt detection and treatment is needed to limit mortality caused by this disease. A recent review of treatment of prostate cancer is by Pirtskhalaishvilig et al. (2001, Cancer Practice 9(6):295).
Increased detection of prostate cancer is due in part to increased awareness and the widespread use of clinical markers such as prostate specific antigen (PSA). Prostate specific antigen is a protein that is produced in very high concentrations in prostate cancer cells. Cancer development results in an altered and subsequent loss of normal gland architecture. This in turn leads to an inability to remove secretions and thus the secretions reach the serum. Serum PSA measurement is one method for screening for prostate cancer.
The current diagnostic and treatment paradigm for prostate cancer is reflected in Clinical Practice Guidelines that are widely available to practicing physicians. The guidelines presented below outline the common approach to the detection and management of prostate cancer.                The Prostate Specific Antigen test is a blood test used to detect prostate cancer in the earliest stages and should be offered annually to men 50 and older with a life expectancy of 10 years or more, and to younger men at high risk for prostate cancer.        The Digital Rectal Exam (DRE) is a test that helps to identify cancer of the prostate, and should be performed on men who are 50 and older and to younger men at high risk for prostate cancer.        A biopsy is recommended for all men who have an abnormal PSA or DRE.        The options for primary management of prostate cancer are surgery, radiation therapy or close observation. Treatment decisions, are based on the aggressiveness of the cancer, the stage of the cancer and the life expectancy of the individual.        Advanced prostate cancer is best managed with hormone therapy.        Radiation therapy can include external and implanted seeds, a procedure known as brachytherapy.        
The PSA test, which facilitates early detection of prostate cancer, has been available in Canada since 1986, although its use did not become widespread until the early 1990's. In 1994 the U.S. Food and Drug Administration (FDA) approved the use of the PSA test in conjunction with DRE as an aid in detecting prostate cancer. The free PSA test (fPSA), a more sensitive test for prostate cancer risk than the standard PSA test, received FDA approval in 1998.
Prostate Specific Antigen is an enzyme made by all prostate cells and normally secreted into semen. Both cancer and a number of benign conditions can change the architecture of the prostate gland so the enzyme escapes into the bloodstream. Once there, PSA can exist in two forms, one that is free-floating and another that is bound to proteins. The standard PSA test measures both forms. There are a number of specialized PSA tests which are used to help differentiate between elevated PSA due to benign conditions and those elevations due to prostate cancer. The free PSA test evaluates the ratio between the PSA that is free in the blood and the total PSA (free and protein bound PSA) in the blood. When the result of the free PSA test is low (i.e. <15%), there is a higher potential that the individual has prostate cancer. The PSA velocity is used to describe the speed at which the PSA value increases over a series of blood tests. The PSA density is used to evaluate the level of PSA in relation to overall size of the prostate gland.
The various PSA tests share some common limitations:                The principal concern is that although diagnostic accuracy has improved with each of the modifications to total serum PSA measurement, none of the forms is specific for prostate cancer.        Each requires a trade-off in specificity for increased sensitivity and vice versa. This trade-off appears to be most advantageous with the proportion of free PSA.        Elevation of PSA may indicate prostate cancer. However, several other common benign conditions, including Benign Prostatic Hyperplasia (BPH), are known to be associated with an elevated PSA.        
Because of the limitations of the PSA test (lack of specificity for prostate cancer and a significant number of “false positive” and “false negative” test results) it remains an investigational tool as opposed to an absolute diagnostic test. Abnormal findings following the administration of the PSA test lead the investigator to perform a biopsy. Physicians are advised to consider a biopsy to confirm a prostate cancer diagnosis when a PSA test reading is at least 4.0 ng/mL, when the PSA level of an individual significantly increases from one test to the next, or when a DRE is abnormal. A biopsy is recommended for all men who have a PSA test result above 10 ng/mL.
The limitations of the PSA test are obvious considering the fact that only one of four individuals biopsied receives results that are positive for the presence of cancerous cells. A Canadian study has estimated the positive predictive value of the PSA test to be as low as 14.4%. This is significant considering the costs associated with a follow-up biopsy as well as the unnecessary pain and anxiety caused for individuals.
Since FDA approval in the U.S., the fPSA test is becoming a follow-up test for men whose PSA falls in a “diagnostic gray zone” of moderately elevated levels (4 to 10 ng/mL).
The digital rectal examination is a simple, inexpensive and direct method of assessing the prostate, but it is unreliable as a sole indicator of prostate cancer. The cancer detection rate is higher with PSA screening than with digital rectal examination (DRE), and the rate increases when the DRE modality is combined with PSA analysis and/or transrectal ultrasound examination (TRUS). DRE has never been shown to be reliable for, staging of prostate cancer. TRUS guided biopsy is required to follow-up on a positive PSA test in order to help confirm the presence or absence of disease in the individual's prostate.
Prostate biopsies are performed to confirm the presence of cancer cells following suspicion raised by the DRE or a positive PSA test. The most commonly reported complications of biopsy consist of traces of blood in the urine, semen or feces. These complications are limited and subside with 2-3 weeks after the procedure. Pain at the time of biopsy is universally reported. Only in exceptional cases is analgesia or sedation required. Most men (>90%) have no significant pain after 24 hours of the biopsy. Prostate biopsies are costly in the U.S. and may be painful or psychologically traumatic. Prostatic biopsy represents the cornerstone of prostate cancer diagnosis.
For prostate cancers in general, biopsies miss cancers at a rate estimated as high as 50 percent. Furthermore, even if a cancer is detected, the location and staging of cancerous cells are not adequately identified.
Thus, there is a need for an improved method for diagnosis and/or detection of cancerous prostate cells.
An important prognostic factor is prostate cancer stage. Cancer staging is performed to determine the extent and spread of cancer in the prostate. Prostate cancer metastasizes by local spread to the pelvic lymph nodes, seminal vesicles, urinary bladder, or pelvic side walls and to distant sites such as bone, lung, liver, or adrenals. The tumor-nodes-metastasis (TMN) staging system is the one most widely used in North America.
The limitations of the biopsy in detecting disease and staging a malignancy is compounded by the fact that prostate cancer is a heterogeneous disease with apparently independent foci of cancer scatter throughout the gland. The cancer foci have different malignant potentials and do not pose equal risks for the individual. Heterogeneity confounds the interpretation of positive prostate biopsies since it is not possible to be certain that the most clinically relevant foci of cancer have been detected.
Approximately only 30% of early stage disease will progress to clinically relevant disease within the lifetime of the individual. It is therefore critical to be able to identify those individuals at risk of progression who would benefit from aggressive therapy while sparing low-risk individuals the morbidity resulting from aggressive treatment of indolent disease. Neither rising PSA nor the presence of cancer cells on biopsy may indicate definitively the presence of lethal disease.
Serum PSA is a valuable cancer marker but cannot be used alone to determine the clinical or pathological stage of prostate cancer or to identify individuals with potentially curable disease. The combination of serum PSA with Gleason Score (a grading system for the classification of adrenocarcinoma of the prostate by observation of the pattern of glandular differentiation) and clinical stage provides a better prediction of the final pathologic stage than do any of these variables separately. Nomograms have been developed and revised to predict the final pathologic stage based on a combination of serum PSA level, Gleason Score, and clinical stage. Because these nomograms only offer a statistical probability of disease organ confinement, further radiographic evaluation has often been used for the individual. However, definitive detection of lymph node metastases with standard anatomical modalities of computed tomography (CT) and magnetic resonance imaging (MRI) has generally proved ineffective, except for the increasingly more uncommon cases with large volume soft-tissue involvement (greater than 1 cm) at presentation.
There is a great need for a new prostate imaging technology that provides for accurate visualization of extraprostatic growth indicative of metastasis. Such a technology would provide physicians with a tool to determine the progression of the cancer and would be extremely valuable in directing treatment options. Spectroscopy significantly improves the diagnosis of extracapsular extension by MRI. However, studies demonstrate that there is high variability in how clinicians interpret the significance of extracapsular extension. Both CT and MRI can be helpful in staging prostate cancer, because they can indicate periprostatic cancer spread, lymph node abnormality and bone involvement, but their sensitivity for revealing cancer extension has limitations.
Imaging techniques such as CT or MRI are unable to distinguish metastatic prostate cancer involvement of lymph nodes by criteria other than size (i.e. >1 cm). Thus, these imaging techniques, being inherently insensitive and non-specific, are insufficient for detection of disease.
The presence of pelvic lymph node metastasis influences both the treatment and the prognosis of individuals with prostate cancer. Lymph node involvement can be assessed surgically. However, incomplete sampling at the time of radical prostatectomy leads to false-negative interpretations in at least 12%, and possibly as many as 33% of individuals with lymph node metastases, because isolated metastases in the external iliac, presciatic, or presacral lymph nodes are outside the boundaries of the standard Pelvic Lymph Node Dissection.
Thus, there is a need for a non-invasive test that is able to identify lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA and/or abnormal DRE and a positive biopsy. This will allow clinicians to reliably differentiate individuals with organ-confined disease from those with metastatic spread to lymph nodes. This will provide the opportunity for the individual and physician to make an informed decision on how to treat the disease and will significantly improve individual health outcome.
Despite considerable research into methods for therapy and disease treatment, prostate cancer remains difficult to treat. Current methods, commonly based on surgery and/or radiation therapy, are ineffective in a significant number of cases. Prostate surgery, for example, holds the potential for damaging nerve tissue and compromising an individual's chances of recovering sexual function. There is a need for an imaging technology that can help to minimize the risks involved in surgery by determining the location of both the cancer and the individual's normal structures.
Furthermore, a new technology that is able to localize cancerous prostate cells that remain following radical prostatectomy would assist physicians in removing all of the cancerous cells from an individual's body with focused treatment such as radiation therapy. A labeled technology that selectively binds prostate cancer cells will allow clinicians to localize any remaining cancer cells following surgery. An additional new technology would provide direct delivery of therapeutic agents, perhaps preventing the need for surgery.
Thus, there is a need for an improved method to detect and/or diagnose lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA and/or abnormal DRE and a positive biopsy.
A substantial amount of work has been put into identifying enzyme or antigen markers, which could be used as sites for detection and/or diagnosis for various types of cancers. These markers could also be used to target cancer cells for treatment with therapeutic and/or cancer cell killing agents. The ideal cancer marker would exhibit, among other characteristics, tissue or cell-type specificity.
A 750 amino acid protein (FIG. 2; SEQ ID NO:22), prostate-specific membrane antigen (PSMA), localized to the prostatic membrane has been identified. The complete coding sequence of the gene (FIG. 1; nucleotides 262 to 2514 of GenBank™ accession number NM—004476) is presented as SEQ ID NO:22. PSMA is an integral Type II membrane glycoprotein with a short intracellular tail and a long extracellular domain. This antigen was identified as the result of generating monoclonal antibodies to a prostatic cancer cell, LNCaP (Horoszewicz et al. (1983) Cancer Res. 43:1809-1818). Israeli et al. (Israeli et al. (1993) Cancer Res. 53:227-230) describes the cloning and sequencing of PSMA and reports that PSMA is prostate-specific and shows increased expression levels in metastatic sites and in hormone-refractory states. Other studies have indicated that PSMA is more strongly expressed in prostate cancer cells relative to cells from the normal prostate or from a prostate with benign hyperplasia. Current methods of targeting prostate specific membrane antigen use antibodies with binding specificity to PSMA. One of the first antibodies described with binding specificity to PSMA was 7E11 (Horoszewicz et al. (1987) Anticancer Res. 7:927-936 and U.S. Pat. No. 5,162,504). Indium-labeled 7E11 localizes to both prostate and sites of metastasis, and is more sensitive for detecting cancer sites than either CT or MR imaging, or bone scan (Bander (1994) Sem. In Oncology 21:607-612).
One of the major disadvantages of the 7E11 antibody is that it is specific to the portion of the PSMA molecule which is present on the inside of the cell (intracellular). Antibody molecules do not normally cross the cell membrane, unless they bind to an extracellular antigen, which subsequently becomes internalized. As such, 7E11 can not be used to target a living prostate cell, cancerous or otherwise. The use of 7E11 for detection or imaging is therefore limited to pockets of dead cells within cancers or tissues with large amounts of dead cells, which cells render available their intracellular portion of PSMA for binding with this antibody.
U.S. Pat. No. 6,107,090, in the name of Neil Bander, and U.S. Pat. No. 6,150,508, in the name of Gerald Murphy et al. describe numerous monoclonal antibodies which recognize the extracellular domain of PSMA, thereby overcoming one of the major drawbacks of the 7E11 antibody. These antibodies, being able to bind to the extracellular domain of PSMA are capable of binding to living prostate cells, thereby allowing a more effective method of diagnosis than 7E11.
As described above, antibodies to PSMA are already in use for diagnostic purposes. For example, PSMA is the antigen recognized by the targeting monoclonal antibody used in ProstaScint™, U.S. Pat. Nos. 5,162,504 and 5,763,202, Cytogen's imaging agent for prostate cancer.
It would be highly desirable to be provided with an improved antibody specific for PSMA and a method for diagnosis and/or detection of cancerous prostate cells.
It would be highly desirable to be provided with a new prostate imaging technology offering accurate visualization of extraprostatic growth indicative of metastasis which would provide physicians with a tool to determine the progression of the cancer and be extremely valuable in directing treatment options.
It would be highly desirable to be provided with a non-invasive test that is able to identify lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA and/or abnormal DRE and a positive biopsy.
It would be highly desirable to be provided with an imaging technology that decreases morbidity by identifying individuals in which surgery is not indicated.
It would be highly desirable to be provided with a new technology that is able to localize cancerous prostate cells that remain following radical prostatectomy which would assist physicians in removing all of the cancerous cells from an individual's body. In addition, it would be highly desirable to be provided with a new technology which would provide direct delivery of therapeutic agents, perhaps preventing the need for surgery.
It would be highly desirable to be provided with an improved method to detect and/or diagnose lymph node metastases in individuals at risk for extraprostatic disease following the detection of elevated PSA.
It would be highly desirable to be provided with a new prostate imaging technology that provides for accurate visualization of extraprostatic growth indicative of metastasis which would provide physicians with a tool to determine the progression of the cancer and be extremely valuable in directing treatment options.
It would be highly desirable to be provided with novel antibodies and their use for detecting, imaging, staging, treating and monitoring of prostate cancer, and/or metastasis thereof. It would also be highly desirable to be provided with novel pharmaceutical compositions for the treatment of prostate cancer.